Shear stimulation of FOXC1 and FOXC2 differentially regulates cytoskeletal activity during lymphatic valve maturation.

Details

Serval ID
serval:BIB_066C420F0AD8
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Shear stimulation of FOXC1 and FOXC2 differentially regulates cytoskeletal activity during lymphatic valve maturation.
Journal
eLife
Author(s)
Norden P.R., Sabine A., Wang Y., Demir C.S., Liu T., Petrova T.V., Kume T.
ISSN
2050-084X (Electronic)
ISSN-L
2050-084X
Publication state
Published
Issued date
08/06/2020
Peer-reviewed
Oui
Volume
9
Language
english
Notes
Publication types: Journal Article
Publication Status: epublish
Abstract
Mutations in the transcription factor FOXC2 are predominately associated with lymphedema. Herein, we demonstrate a key role for related factor FOXC1, in addition to FOXC2, in regulating cytoskeletal activity in lymphatic valves. FOXC1 is induced by laminar, but not oscillatory, shear and inducible, endothelial-specific deletion impaired postnatal lymphatic valve maturation in mice. However, deletion of Foxc2 induced valve degeneration, which is exacerbated in Foxc1; Foxc2 mutants. FOXC1 knockdown (KD) in human lymphatic endothelial cells increased focal adhesions and actin stress fibers whereas FOXC2-KD increased focal adherens and disrupted cell junctions, mediated by increased ROCK activation. ROCK inhibition rescued cytoskeletal or junctional integrity changes induced by inactivation of FOXC1 and FOXC2 invitro and vivo respectively, but only ameliorated valve degeneration in Foxc2 mutants. These results identify both FOXC1 and FOXC2 as mediators of mechanotransduction in the postnatal lymphatic vasculature and posit cytoskeletal signaling as a therapeutic target in lymphatic pathologies.
Keywords
cell biology, developmental biology, mouse, lymphatic endothelial cell, lymphatic valve, mesentery
Pubmed
Web of science
Open Access
Yes
Create date
10/06/2020 15:20
Last modification date
15/08/2020 5:26
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